Early pregnancy failure (EPF) is the leading cause of morbidity in pregnancy. Effective and timely treatment for EPF can decrease the personal and societal costs that are associated with this burdensome pregnancy complication. Patient and provider interest in non-surgical options for management of early pregnancy failure has led to the wide-spread use of prostaglandin analogues, specifically misoprostol, for uterine evacuation. However, the effectiveness of the most commonly used first-line medical treatment for EPF is low (60%-70% complete expulsion for embryonic/fetal demise and anembryonic gestation). Given the advantages of non- surgical management for this high-incidence condition, new approaches to reduce the frequency of treatment failures are essential. Mifepristone, a competitive progesterone and glucocorticoid receptor antagonist, blocks the cellular effects of progesterone and glucocorticoids. Our preliminary data strongly suggest that the addition of mifepristone to the medical treatment protocol will significantly increase the success rates of medical treatment for women with miscarriage. In the present proposal, we aim to test a treatment regimen with the goal of establishing a new standard of care for the nonsurgical management of early pregnancy failure. Our two-part approach includes 1) a multicenter randomized placebo-controlled double-masked trial of mifepristone and misoprostol versus placebo and misoprostol to test the comparative effectiveness of the two regimens, and 2) an investigation of trophoblastic and endometrial biomarkers in the maternal serum to help predict which women will achieve success with medical management of embryonic/fetal demise and anembryonic gestation. This project combines population-based and individual-level approaches to significantly advance an under-evaluated but extremely common disorder in human reproduction.